Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer

Abstract

Introduction: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib.

Methods: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment.

Results: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR.

Conclusions: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

FIGURE 1.

SQSTM1-NTRK1 fusion transcripts detected by AMP in a NSCLC. (A) Contiguous reads from amplified transcripts mapped to the locations of SQSTM1 on chromosome 5 and NTRK1 on chromosome 1 (red arrowheads). (B) Visualization of subset of sequence read pileup showing fusion reads. The y axis represents read coverage. The x axis represents reference bases and their respective codons below. Shown in gray are read portions corresponding to the randomly ligated universal adapter end with staggered distribution of reads and differing start positions. Shown in blue are read portions corresponding to the anchored end targeted with GSP1 and GSP2. The fusion is in-frame with respect to both transcripts. (C) Schematic drawing of gene fusion involving SQSTM1 and NTRK1. TM, transmembrane domain. Not drawn to scale. (D) FISH confirmation SQSTM1-NTRK1 rearrangement showed individual 3’ (red only) probe signals that represent a region downstream of the NTRK1 gene along with normal paired green and red signals that represent non-rearranged alleles. White arrows highlight representative red only signals.

FIGURE 2.

Partial response to entrectinib. Horizontal (A) and coronal (B) images of the chest at day -7 (baseline scan), day 26 (C, D), and day 155 (E, F) on entrectinib.

FIGURE 3.

Complete response of brain metastases to entrectinib. (A-C) Baseline head CT scan at day -7 demonstrating metastases (green arrows) in the right thalamus (A), left occipital lobe (B) and left cerebellum (C). (D-I) Restaging head CT scans at day 26 (D-F) and day 155 (G-I) on entrectinib.

FIGURE 4.

Trk signaling. (A) Schematic diagrams showing wild-type TrkA, TrkB or TrkC protein, top, and showing an oncogenic fusion involving a partner gene that contains a dimerization domain and the kinase domain of TrkA, TrkB or TrkC, bottom. Of note, the fusion shown here includes the transmembrane (TM) domain, though Trk fusion proteins that lack the TM domain have also been described. (B) In the absence of ligand, left, Trk proteins do not dimerize or activate downstream signaling pathways. In the presence of ligand (red circle), Trk proteins dimerize, leading to downstream pathway activation. Double line represents the cell membrane. (C) Fusion oncogenes dimerize in a ligand-independent manner, leading to constituative activation and downstream signaling. Proteins and their domains are not draw to scale.